rs863225251

Variant names:

• chr3-184355751-G-ATGAGCAGT
• rs863225251
• NM_004366.6:c.1113delCinsACTGCTCAT

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_004366.6(CLCN2):​c.1113delCinsACTGCTCAT​(p.Leu372CysfsTer6) variant causes a frameshift, synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. T371T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CLCN2 NM_004366.6 frameshift, synonymous
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: -0.572
• Publications: 1 publications found

Genes affected

CLCN2 (HGNC:2020): (chloride voltage-gated channel 2) This gene encodes a voltage-gated chloride channel. The encoded protein is a transmembrane protein that maintains chloride ion homeostasis in various cells. Defects in this gene may be a cause of certain epilepsies. Four transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2012]

CLCN2 Gene-Disease associations (from GenCC):

• leukoencephalopathy with mild cerebellar ataxia and white matter edema

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• epilepsy, idiopathic generalized, susceptibility to, 11

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• familial hyperaldosteronism type II

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
• epilepsy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-184355751-G-ATGAGCAGT is Pathogenic according to our data. Variant chr3-184355751-G-ATGAGCAGT is described in ClinVar as Pathogenic. ClinVar VariationId is 217787.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004366.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN2	NM_004366.6	MANE Select	c.1113delCinsACTGCTCAT	p.Leu372CysfsTer6	frameshift synonymous	Exon 11 of 24	NP_004357.3
	CLCN2	NM_001171087.3		c.1113delCinsACTGCTCAT	p.Leu372CysfsTer6	frameshift synonymous	Exon 11 of 24	NP_001164558.1
	CLCN2	NM_001171089.3		c.1113delCinsACTGCTCAT	p.Leu372CysfsTer6	frameshift synonymous	Exon 11 of 23	NP_001164560.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN2	ENST00000265593.9	TSL:1 MANE Select	c.1113delCinsACTGCTCAT	p.Leu372CysfsTer6	frameshift synonymous	Exon 11 of 24	ENSP00000265593.4
	CLCN2	ENST00000344937.11	TSL:1	c.1113delCinsACTGCTCAT	p.Leu372CysfsTer6	frameshift synonymous	Exon 11 of 24	ENSP00000345056.7
	CLCN2	ENST00000430397.5	TSL:1	n.54delCinsACTGCTCAT		non_coding_transcript_exon	Exon 2 of 13	ENSP00000396231.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	CLCN2-related disorder (1)
-	-	-	Leukoencephalopathy with mild cerebellar ataxia and white matter edema (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.57

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs863225251; hg19: chr3-184073539;